1. Field of the Invention
The present invention relates to DNA vaccines and theirs uses in treating cancers. More particularly, the present invention relates to DNA vaccines for treating solid tumors such as bladder cancer, lung cancer, prostate cancer, melanoma and kidney cancer.
2. Description of Related Art
A vaccine is one of the most effective, safe, nontoxic and economical ways to prevent disease and to control the spreading of disease. Conventional vaccines are a form of immunoprophylaxis given before disease occurrence to afford immunoprotection by generating a strong host immunological memory against a specific antigen. The primary aim of vaccination is to activate the adaptive specific immune response, primarily to generate B and T lymphocytes and/or natural killer cells (NK cells) against specific antigen(s) associated with the disease.
Similarly, cancer vaccines aim to generate immune response against cancer tumor associated antigens. Cancers can be immunogenic and can activate host immune response capable of controlling the disease and causing tumor regression. Many protein/glycoprotein tumor-associated antigens have been identified and linked to certain types of cancer, such as MAGE-3, MAGE-1, gp100, TRP-2, ras, β-catenin, gp43 and HSP-70, just to name a few.
There is a report regarding the successful use of live Mycobacterium bovis bacillus Calmette-Guérin (M. BCG) in preventing the progression and recurrence of superficial bladder cancer after transurethral resection of the bladder tumor (see Morales A. et al., “Intracavitary bacillus Calmette-Guérin in the Treatment of superficial Bladder Tumors”, (1976) J. Urol. 116:180-183). However, this approach has not been completely satisfactory due to a number of problems, for example, it is not effective to all patients, a significant 30-40% of patients either does not respond to BCG therapy or shows adverse side effects such as fever, granulomatous prostatitis, pneumonitis, hepatitis and BCG sepsis (see Vegt P. D. et al., “Bacillus Calmette-Guérin Tice and Bacillus Calmette-Guérin RIVM treatment in pTa-pT1 papillary carcinoma and carcinoma in situ of the bladder”, (1995) J. Urol. 153:929-933; Suzuki S. et al., “Complications of Bacillus Calmette-Guérin Therapy In Superficial Urothelial Cancer: Clinical Analysis And Implications”, (2002) Int. J. Clin. Oncol. 7:289-293). The use of nonviable heat-inactivated BCG and BCG subfractions in reducing adverse effects caused by BCG therapy has also been suggested (see Morales et al, “Mycobacterial Cell Wall Extract For Treatment of Carcinoma in situ of the Bladder”, (2001) J. Urol. 166:1633-1637), whereas others point out that treatments with viable organisms is more effective (see Bohle et al, “Dissecting the Immunobiological Effects of Bacillus Calmette-Guérin (BCG) In Vitro: Evidence of a distinct BCG-activated Killer (BAK) Cell Phenomenon”, (1993) J. Urol. 150:1932-1937). According to the results of a recent study, combination of BCG therapy and the activation of cytokines pathways within a host to generate interferon such as interferon α-2b, interleukin-2, and interferon α may further enhance the efficacy of BCG therapy without increasing its adverse effects (see Stavropoulos et al., “Intravesical Instillations of Interferon γ In The Prophylaxis of High Risk Superficial Bladder Cancer—Results of A Controlled Prospective Study”, (2002) J. Urol. Nephrol. 36:218-222). Unfortunately, the development of a tumor vaccine based on this approach has failed (see Lamm et al., “Immunotherapy Of Murin Bladder Cancer By Irradiated Tumor Vaccine”, (1991) J. Urol. 145:195-198). Therefore, there exists a need for developing an improved DNA cancer vaccine, which is more potent than the current BCG immunotherapy and without its adverse side effects, for the treatment of mammalian cancers, especially human bladder cancer (see Lee et al., “Immunotherapy for bladder cancer using recombinant BCG DNA Vaccines and Interleukin-12 DNA Vaccine”, (2004) J. Urol., 171:1343-1347; see Yu et al., Antitumor effects of recombinant BCG and interleukin-12 DNA Vaccines on the xenografted murine bladder cancer (2004) Urology, 63:596-601; see Lee et al., “Treatment of bladder carcinomas using recombinant BCG DNA Vaccines and electroporative gene immunotherapy”, Cancer Gene Ther (2004) 11:194-207).